1. Enhance the pharmacist’s knowledge of erectile dysfunction and the multiple treatment options, focusing on pharmacologic interventions.

Provide the pharmacist with a guide to counseling patients with erectile dysfunction.

1. State the prevalence of erectile dysfunction (ED) in the general population and identify high risk patients.

 

 

Describe the pathophysiology of ED and list the different types of ED.

Explain several common diagnostic techniques.

Discuss the individual drug therapies used to treat ED.

List new pharmacologic advances, their place in therapy, and advantages/disadvantages.

Describe a counseling session for a patient with ED.

INTRODUCTION

The inability of the male to attain and maintain an erection sufficient to allow sexual intercourse is termed erectile dysfunction.¹ Erectile dysfunction is but one condition of a number of male sexual dysfunctions. Other sexual problems that males could encounter include reduced sexual desire or changes in libido, and orgasmic and ejaculatory dysfunction. The term was used in the literature until about 1990 to mean any of the dysfunctions, including erectile dysfunction.

Since the 1980s there has been an increased awareness by both patients and health care providers of the prevalence of and treatment options for erectile dysfunction.² Pharmacists must be aware of new pharmacotherapeutic interventions available for patients with erectile dysfunction. Because age plays an important role in the development of erectile dysfunction, the pharmacist will see more patients than ever before with the problem as the baby-boomer population ages.³ Serving as an information source for current and emerging therapies for both physicians and patients is an essential role of the pharmacist. The pharmacist can also serve the patient in helping to identify erectile dysfunction and referring patients for medical help.

PREVALENCE

The most common health disorder to afflict older men is not hypertension or arthritis but erectile dysfunction.^3,4 Male erectile dysfunction has been characterized by the degree of dysfunction, and estimates of prevalence will vary depending on the definition of erectile dysfunction used in the study. Erectile dysfunction usually consists of partial erectile failure (difficulty in obtaining the initial erection or in achieving adequate rigidity) rather than complete lack of penile rigidity.⁵ A common complaint is early detumescence, or loss of erection before ejaculation.

Today, it is estimated that between 10 to 20 million males are affected with severe erectile dysfunction in the United States. If individuals with minimal dysfunction are included, the estimate increases to 30 million.^1,6 A recent and extensive population-based survey confirmed the high prevalence of this disorder.⁴ Feldman et al based results on a sample of 1290 males aged 40 to 70 years of age. The prevalence of erectile dysfunction was 52% in older males, with an incidence of 5% at age 40 years and 15% at 70 years of age. Other reports showed that 34% of male patients in primary care clinics reported some degree of erectile dysfunction.⁷ Despite the high prevalence of erectile dysfunction, less than 5% of men receive treatment.⁸

IMPACT OF ERECTILE DYSFUNCTION

In the United States in 1985, erectile dysfunction accounted for 400,000 outpatient visits to physicians and 30,000 hospital admissions, resulting in total direct costs of $146 million.⁴ In terms of human cost, there is evidence that erectile dysfunction can influence the patient and partner. Although erectile dysfunction is usually considered a relatively benign disorder, it has a dramatic impact on the quality of life of many men as well as their sexual partners.^1,4,9 The diagnosis of erectile dysfunction may be understood as the presence of a condition limiting choices for sexual interaction and possibly limiting opportunity for sexual satisfaction.¹ The impact of erectile dysfunction depends on the dynamics of the relationship of the individual and his sexual partner and their expectation of performance. Some patients will modify their sexual behavior in order to accommodate the condition and maintain sexual satisfaction. However, more men are not accepting erectile dysfunction as normal and seek ways to return to normal sexual functioning.

Erectile dysfunction may be associated with depression, increased anxiety and poor self-esteem in affected patients.^1,10 Erectile dysfunction may diminish the willingness to initiate sexual relationships because of fear of inadequate sexual performance or rejection. Withdrawal from these relationships may have a negative effect on a person’s overall health.

ANATOMY AND PHYSIOLOGY

The erectile tissue of the penis consists of three chambers: the paired corpora cavernosa and the corpus spongiosum that run along the length of the penis. The corpus spongiosum, located ventrally in the penis, surrounds the urethra until the end where it enlarges to form the glans penis. The paired corpora cavernosa are found on the dorsal side of the penis. They consist of two caverns that lay side by side. A thick fibrous sheath (tunica albuginea) encloses each corporeal body. Blood flows freely between the corpora through connector vessels allowing them to function as a single unit. The tunica albuginea prevents communication between the corpus spongiosum and the corpora cavernosa.^11,12 The tissue within the corporeal erectile chambers is a trabecular framework consisting primarily of bundles of smooth muscle fibers and other cells in a collagenous matrix. A criss-crossing pattern creates the vascular spaces known as lacunar spaces or sinusoids which are lined by endothelial cells surrounded by smooth muscle cells.

The blood supply to the erectile tissues is derived from the penile arteries, which are branches of the internal pudendal arteries. Each penile artery gives rise to cavernous arteries which pierce the tunica albuginea and give off multiple terminal helicine arteries. The helicine arteries open directly into the sinusoidal spaces. The smooth muscle found throughout these sinusoidal spaces as well as the arterial smooth muscle is under alpha-adrenergic control and is contracted when the penis is flaccid, preventing blood from entering the corporal chambers. When the smooth muscle relaxes, blood enters the chambers to cause an erection.

The penis has a rich venous drainage. The peripheral sinusoidal spaces of the corpora cavernosa are drained by small venules that coalesce to form venous plexuses beneath the tunica albuginea. These plexuses unite and drain into the short emissary veins which pass through the tunica albuginea and ultimately drain into the deep dorsal vein. Surrounding the venules are smooth muscle bundles that relax during the flaccid state.

Erection is a vascular event initiated by either psychological stimuli, such as sexual perception or desire, or genital stimulation. These stimuli are processed by the hypothalamus, which orchestrates the sympathetic and parasympathetic response.³ Sympathetic nerves travel via the hypogastric nerve and parasympathetic nerves travel via the pelvic nerve to the pelvic plexus. The pelvic plexus gives rise to the cavernous nerves which travel along the posterolateral aspects of the prostate (directly adjacent to the prostatic capsule) and continue on both sides of the urethra.^9,13,14

Parasympathetic stimulation causes relaxation of the smooth muscle of the trabecular meshwork in the corporal cavities and the helicine arteries allowing increased penile blood flow. This action is thought to be controlled by cholinergic and nonadrenergic, noncholinergic mechanisms and also by the action of an endothelium-derived relaxing factor or nitric oxide. Nitric oxide is currently thought to be the primary nonadrenergic-noncholinergic messenger. The signals produced by nitric oxide in the trabecular smooth muscle may be mediated through its stimulation of guanylate cyclase and the production of cyclic guanosine monophosphate (cGMP) which would then function as a second messenger intracellularly.¹⁵ Vasoactive polypeptide is thought to be a co-mediator (with nitric oxide) of smooth muscle relaxation and may help regenerate nitric oxide, thereby maintaining erection. ^1,16-20 Both cAMP and cGMP are inactivated by type-V phosphodiesterases.

As blood flows into the lacunar spaces, the corporal cavities enlarge. Their walls compress the outlet venules against the tunica albuginea, a process referred to as the corporal veno-occlusive mechanism. As the venules are compressed against the tunica albuginea, penile pressure approaches arterial pressure, causing rigidity. Once this state is achieved, arterial inflow is reduced to a level that matches venous outflow. A steady state ensues in which the inflow and outflow of blood are equalized. After ejaculation, adrenergic stimulation causes smooth muscle contraction of the trabecular meshwork and the helicine arteries stopping blood flow into the corporal cavities causing flaccidity. For a time following ejaculation no erection can be stimulated. This is referred to as the refractory period and can last from a few minutes in younger males to as long as 12 to 24 hours in older men.⁵

PATHOPHYSIOLOGY

Erectile dysfunction can occur following disruptions of one or more of the coordinated mechanisms required for normal erectile function. There are two categories (depending on the dominant problem): organic (neurologic or vascular) and psychogenic. While most patients with erectile dysfunction have some degree of an organic or physiologic problem, psychogenic aspects of low self-esteem, anxiety, and poor partner communication and conflict are often important contributing factors. In the majority of patients, erectile dysfunction appears related to multiple factors acting together, although one set of factors may predominate.

Psychogenic

Psychogenic cause of erectile dysfunction refers to the inability to obtain and/or sustain an erection without underlying organic pathology. At one time, psychogenic causes were considered to be responsible for 90% of all cases.¹¹ With the availability of better diagnostic tests, psychogenic causes are now believed to account for 10 to 50% of cases of erectile dysfunction.²¹ Life stresses such as a change in social status, divorce, death of spouse, loss of job, or family problems, can cause or contribute to erectile dysfunction. Depression, anxiety, and relationship problems can impair erectile functioning. Depression has been reported to be present in between 8 and 33% of patients with erectile dysfunction.²² Other causes of psychogenic erectile dysfunction include performance anxiety and widower’s syndrome. Once a patient experiences a partial or total lack of erectile response, further attempts at sexual contact may produce anxiety which further contributes to lack of response. This is referred to as performance anxiety. Widower’s syndrome refers to the male who attempts to engage in sexual contact after the death of a spouse but experiences erectile dysfunction. Often guilt or anxiety contribute to cause erectile dysfunction in these cases.²³

Health care providers are increasingly recognizing the organic causes of erectile dysfunction. However, clinicians must also remember that in many cases, some degree of both psychogenic and organic causes coexist.

Neurogenic

Primary neurologic disorders are the cause of erectile dysfunction in approximately 10% of cases.²⁴ Damage to the autonomic pathways originating in the central nervous system which innervates the penis may eliminate psychogenic erection. Lesions of the somatic nervous pathways may impair reflexogenic erections and may interrupt tactile sensation needed to maintain psychogenic erections. Spinal cord lesions may produce varying degrees of erectile failure depending on the location and completeness of the lesions.²¹

The majority of these disorders involve primary injury to the spinal cord.²⁴ The nature, location, and extent of the lesion will determine the degree of impairment.¹ Lower spinal cord lesions have a higher rate of impaired reflex-related erections. In general, patients with incomplete lesions achieve better erectile function than those with complete lesions.

Multiple sclerosis is associated with a high incidence of erectile dysfunction. Partial or total erectile dysfunction has been observed in between 50% to 70% of men with an established diagnosis of multiple sclerosis.^25,26 Other conditions include cerebrovascular disease, stroke, Parkinson’s disease, and Alzheimer’s disease. These conditions may involve centers of the brain associated with sexual function.

Endocrinologic

The majority of these disorders produce either a deficiency of serum testosterone or elevation of serum prolactin levels.²⁴ Serum testosterone levels less than 250 ng/dL are often associated with decreased libido and with problems of obtaining and maintaining erections. Serum prolactin levels higher than 50 ng/ml are usually associated with decreased serum testosterone values. However, levels higher than 25 ng/ml may be associated with problems of erection independent of any decrease in serum testosterone. Patients with hypothyroidism and primary adrenal insufficiency also may have diminished serum testosterone levels.

Androgens are necessary but not essential for normal libido, and their role in erectile function is unclear.²⁷ Testosterone is needed for maintenance of virilization, libido, potency, secondary sexual characteristics, and preservation of muscle and bone mass. Lack of testosterone can produce poor sexual performance.²⁶ Patients with low levels of testosterone may achieve erections triggered by visual or sexual stimulation comparable to patients with normal testosterone levels.

Systemic diseases may lead to hypogonadism and low testosterone levels. Successful treatment of the underlying conditions can restore libido and erectile function in patients without underlying organic causes. Examples of conditions are listed in Table 1.

Vascular

The two types of vascular diseases identified as primary causes of erectile dysfunction are atherosclerotic disease of the penile arteries and venous leaks. They often occur to some degree simultaneously. Vascular disease is estimated to cause erectile dysfunction with an incidence of 10 to 20% overall, rising to 50% of mean age 50 years and older.^24,29 Arterial insufficiency may result from trauma or congenital anomalies, but the majority of cases can be attributed to a generalized process of atheosclerosis.^21,22 Patients with atherosclerosis of the penile artery have an increased chance of developing atherosclerosis in other organs. In one study, 23% of males who have erectile dysfunction due to vascular problems had a myocardial infarction or stroke in the two years following diagnosis compared to only 4.5% occurrence in patients with normal function.³⁰

Hypertension and diabetes are conditions that are risk factors for developing cardiovascular disease. Not only do these conditions contribute to the atherosclerotic process, erectile dysfunction may be worsened by medications used to treat the conditions and will be discussed in more detail below. However, diseases such as hypertension may induce erectile dysfunction independent of the medications used to treat the condition.³¹

Irregularities with the venous system may also contribute to erectile dysfunction. Some patients have shunting of blood from the corporal bodies directly to medium-sized veins, so the sacs never fill completely. This is called venous leakage or veno-occlusive disorder. Moderate to severe failure of the venous closure mechanism has been shown to be either the main or concomitant cause of erectile dysfunction in 90% of patients who do not achieve an adequate erection with intracavernous vasoactive agents.^32,33

Peyronie’s Disease

Peyronie’s disease results from an inflammatory process of unknown origin affecting the tunica albuginea. Patients with Peyronie’s disease develop a firm, painless plaque or band, usually on the dorsum of the penis.²¹ In Peyronie’s disease, development of fibrotic plaque along the tunica albuginea of the corpora cavernosa can cause pain and bending of the penis with erection. When severe, the angulation of the penis prevents penetration of the vagina. Pain may occur with erection during sexual activity.

Diabetes

The prevalence of erectile dysfunction in the diabetic population ranges from 27% to 59%, depending on the age and the extent of the disease and is the most common organic cause.^6,34 There are likely multiple causes of erectile dysfunction in patients with diabetes. Vascular factors, neuropathy, hormonal imbalance, and psychogenic abnormalities together or individually are responsible. The most common cause is vascular or neuropathic, with psychogenic dysfunction arising secondarily.³⁵ Heightened corporal smooth muscle tone has been attributed as another cause.²¹

Chronic renal failure

Erectile dysfunction is seen in up to 40% of men with chronic renal failure and can develop before or after the initiation of dialysis.¹ There are multiple possible explanations which include hypoxemia due to anemia, hyperprolactinemia, hypogonadism, hyperparathyroidism, and zinc deficiency. Studies have shown that treatment of anemia of chronic renal failure with erythropoietin improves sexual function. Increases in tissue oxygenation could improve erectile functioning by promoting nitric oxide release and sustaining corporal smooth muscle relaxation.^36,37

Drugs

Drugs, both those used for prescriptive purposes and those used "recreationally" can cause erectile dysfunction. Table 2. There are multiple mechanisms by which medications exert a negative influence on the erectile process. Regardless of the mechanism, drug-induced erectile dysfunction is common.³⁸ Overall incidence of drug-associated erectile dysfunction may be 25% of affected patients.²¹

Noncompliance with a drug regimen is a major problem when the patient associates dysfunction with a medication. Conversely, the insidious development of drug-induced dysfunction may mask the association to both the physician and the patient.²⁴ If the drug depresses libido initially before the development of erectile dysfunction, then it is even less recognizable. Lastly, to further confuse the issue, the chronic disease being treated with the medication may also be a cause erectile dysfunction.

Antihypertensives such as beta-blockers, thiazide diuretics, reserpine, hydralazine, guanethidine, clonidine, acetazolamide, methyldopa, and some calcium channel blockers have been implicated. There are several hypothesized mechanisms by which these agents cause or contribute to erectile dysfunction. Most are related to the agent’s mechanism of action. Diuretics induce hypokalemia, blood volume loss, and have a direct effect on penile smooth muscle.^31,39 Sympatholytic antihypertensives are frequently associated with erectile dysfunction, with most studies showing between a 20 and 30% incidence.³⁹ Centrally acting agents cause dysfunction of the tumescence mechanism. Examples of such drugs include propranolol, methyldopa, clonidine and reserpine. Peripheral sympatholytics such as guanethidine, reserpine, and related rauwolfia alkaloids are reported to cause both ejaculatory disturbance and erectile dysfunction.^31,39 Additionally, antihypertensive agents in general lower systemic blood pressure which may reduce penile blood flow and result in erectile dysfunction.⁴⁰ Although angiotensin-converting enzyme inhibitors and calcium channel blockers may be alternative agents with little direct effect on the erection process, any drug that lowers blood pressure in a patient with existing atherosclerotic disease may induce erectile dysfunction.

Some medications may cause hormonal imbalances which lead to erectile dysfunction.³⁹ Spironolactone, a competitive aldosterone antagonist diuretic, is known to cause gynecomastia, decreased libido and erectile failure in 4 to 30% of patients, largely because of its antiandrogenic action. Beta-blockers cause a reduction in serum testosterone, with propranolol having the greatest effect. Methyldopa and reserpine may also elevate prolactin levels. Ketoconazole is known to block androgen synthesis. Digitalis decreases serum testosterone and increases serum estradiol levels, while cimetidine in higher doses can act as weak androgen antagonist by blocking androgen receptors. Some agents may cause elevation of plasma prolactin levels such as phenothiazines, opiates, cimetidine, and haloperidol.

Tricyclic and tetracyclic antidepressants, lithium, and monoamine oxidase inhibitors (MAOI) may influence central nervous system mechanisms of normal erectile response.⁴¹ Many psychotropic drugs have been associated with erectile dysfunction and other forms of sexual dysfunction. Erectile dysfunction usually occurs shortly after the initiation of therapy, not uncommonly within 24 hours. Thioridazine and chlorpromazine appear to be the worst offenders, with an incidence as high as 40 to 60%. In some cases, decreasing the dose alleviates the problem, but switching to another agent is often required.

Smoking , cocaine, marijuana, and ethanol can contribute to erectile dysfunction. Smoking, especially cigarettes, carries several risks. The long-term effect is to produce arterial blockage in peripheral circulation. There may also be a direct effect on penile tissue. Long-term alcohol overuse can cause damage to the nerve conduction mechanisms, especially in the presence of other diseases.¹

DIAGNOSIS

All patients with erectile dysfunction should undergo an evaluation that includes a medical and detailed sexual history (including practices and techniques), a physical examination, a psychosocial evaluation, and basic laboratory studies. Beyond these diagnostic procedures, additional testing may not be necessary based on the goals of the patient and his sexual partner. Using goal-directed intervention, the patient and partner make informed choices that provides the direction for the type of diagnostic tests undertaken.^42,43

The Interview

A sexual history includes examining the sexual expectations and motivations and should be obtained from the patient and sexual partner whenever possible. A written questionnaire may be helpful, but is not a substitute for the interview. Psychosocial testing of the patient may include administering one of a number of standardized self-report instruments to assess sexual and erectile dysfunction.²⁴

The interview is required to accurately define the patient’s complaint and to distinguish between erectile dysfunction and other forms of sexual dysfunction.¹ Specific questions focus on perceptions of erectile dysfunction, including the nature of onset, frequency, quality, duration of erections, the presence of nocturnal or morning erections, and the ability to achieve sexual satisfaction. Psychosocial factors should be explored, including specific situational circumstances, performance anxiety, the nature of sexual relationships, details of current sexual techniques, expectations, motivation for treatment, and the presence of problems in the relationship with the patient’s sexual partner.

A general medical history is important for identifying specific risk factors that may be the cause of or contribute to erectile dysfunction. A detailed medication history is vital, including prescriptions, nonprescription medications including vitamins as well as alternative or complimentary medications (home remedies or herbal medications). As well, a history of illicit drug use such as cocaine or excessive alcohol consumption must be included.

Physical exam

The physical exam should include assessment of male secondary sex characteristics, femoral and lower extremity pulses, and a focused neurological examination, including perianal sensation, anal sphincter tone, and bulbocavernosus reflex.¹ More extensive neurological examinations lack normative data and appear at this time to be of limited clinical value. Examination of the genitalia includes evaluation of testis size and consistency, palpation of the penis to determine the presence of Peyronie’s plaques, and a digital rectal examination of the prostate with assessment of anal sphincter tone.

Labs

Generally, laboratory tests would include a morning serum testosterone level and possibly a serum prolactin level. A low testosterone level should be repeated together with assessment of luteinizing hormone, follicle-stimulating hormone, and prolactin levels to rule out hormonal reasons for erectile dysfunction. Other labs that may be helpful include a complete blood count, urinalysis, creatinine, lipid profile, fasting blood sugar, and thyroid function tests.²⁴ One recent report recommended that testosterone levels be determined only in cases of low sexual desire and abnormal physical examination before age 50 years, but that it be measured in all men older than 50. Prolactin should be determined only in cases of low sexual desire, gynecomastia, and /or testosterone less than 4 ng/ml.⁴⁴

Nocturnal penile tumescence testing

At night, primarily during REM sleep, males have spontaneous erections. Sleep erections are an androgen-dependent phenomenon presumed to reflect the potential for the penis to become rigid without being affected by psychological stressors.³⁷ Sleep erections can be monitored either in a sleep laboratory or with portable equipment in the patient’s home. A number of erectile parameters are measured that provide information on the quality and quantity of nocturnal erections using specialized equipment. Nocturnal penile tumescence testing is not indicated for routine use.¹ However, it may be useful in patients who report a complete absence of erections or when a primary psychogenic origin is suspected. Various methods and devices are available for the evaluation, but their clinical usefulness is restricted by limitations of diagnostic accuracy and availability of normative data.¹ The RigiScan^® device (Dacomed Corp, Minneapolis, MN) is often used in clinical studies and specialty clinics and has been shown to be able to differentiate between patients with organic and non-organic erectile dysfunction.⁴⁵

Intracavernous injection

Depending on the treatment intervention agreed upon between the patient and physician, intracavernous injection of vasoactive substances may be used to further identify the underlying pathology causing erectile dysfunction.^1,24 If an intracavernous injection in smaller test doses produces a rigid or nearly rigid erectile response, it may be assumed that there is adequate arterial and veno-occlusive function. This then suggests that one therapeutic option available to the patient is intracavernous injection therapy. The technique may also help to differentiate a vascular from a primarily neuropathic or psychogenic problem. A partial erection is likely due to mixed neurogenic and vasculogenic cause; a fully rigid erection suggests a neurogenic or psychogenic cause. Patients who have an inadequate response to intracavernous injection may be candidates for further vascular testing if the patient-desired intervention warrants. Caution must be used, however, when interpreting the results of a failed response. This may occur as the result of anxiety rather than physiologic causes.

Radiographic/Ultrasonography

A number of other invasive and noninvasive studies can be performed in selected patients. These procedures can further define arterial and/or venous system disorders. They include pharmacological duplex ultrasonography, pharmacological dynamic infusion caverosometry-cavernosography, and pharmacological pelvic-penile angiography. The clinical effectiveness of these studies is limited by several factors, including lack of normative data, operator experience, variable interpretation of results, and poor predictability of therapeutic outcomes of arterial and venous surgery.^1,46

INTERVENTIONS

General considerations

The patient and his partner must be well informed about all therapeutic options, including their effectiveness, possible complications, and costs. The treatment of erectile dysfunction must be patient-guided for the most part. It is important for the physician and pharmacist to have an understanding of the patient’s sexual problems, expectations, and desires. In the past, the physician judged a positive outcome for the treatment of erectile dysfunction as a rigid erection that was satisfactory for intercourse. The trend now is to assess what the patient’s concept of a successful outcome should be. Many patients may be satisfied with the ability to attain an erection that may or may not be satisfactory for successful intercourse at every attempt. Thus, patient desires and treatment outcomes have shifted the response end point.⁴⁷ The principle of goal-directed therapy is to minimize unnecessary or invasive investigation, and proceed as expeditiously as possible to sexual function restoration, unless the screening history and physical examination (or patient’s preference) indicate that an underlying cause must be sought.⁴⁸

It is important for the health professional to look for the obvious, i.e., reversible medical problems that may contribute to erectile dysfunction. The treatment plan should include identifying medications that may cause erectile dysfunction, with consideration for substitution of medications with a lower incidence of erectile dysfunction. Other lifestyle modifications would include smoking cessation and reduction in alcohol intake when appropriate.

Psychotherapy

The goal of psychotherapy is to restore erectile function to patient-desired level by surmounting the psychological barriers that preclude mutual sexual satisfaction.³⁷ Psychotherapy may be particularly useful for some patients with non-organic erectile dysfunction. Psychotherapy can also be used as an adjunct to other therapies directed at the treatment of organic erectile dysfunction.⁴⁹

Psychotherapy techniques used today have their origins in treatment models developed decades ago. Before the 1980s, there were three psychological models for erectile dysfunction treatment. They include psychoanalytically-based treatment, focusing on the patient’s early-life roots of sexual conflicts; behavioral treatment, focusing on systematic desensitization of the patient’s current sexual anxiety; and sex therapy, a psychoeducational treatment for couples develop by Masters and Johnson, which emphasizes re-educating couples to a sensual, mutual sexual experience through a coordinated series of homework assignments and counseling sessions.² The latter is often referred today as sensate focus therapy. This behavioral approach forbids sexual intercourse for a time, and the couple is trained to focus on other ways of enhancing enjoyment.²² Psychotherapy and behavioral therapy have been reported to relieve depression and anxiety as well as to improve sexual function. However, outcome data of psychological and behavioral therapy have not been quantified, and evaluation of the success of specific techniques used is poorly documented.¹

Pharmacotherapy

ORAL THERAPY
Sildenafil—Sildenafil (Viagra™, Pfizer) is an oral agent that recently received approval from the Food and Drug Administration for the treatment of erectile dysfunction. Sildenafil’s mechanism of action is to block type-V cGMP phosphodiesterase from inactivating cAMP and cGMP in the smooth muscle of the corporal cavernosa allowing smooth muscle relaxation. Through this mechanism, it is believed that nitric oxide activity is then increased in the tissue. This, in turn, increases blood flow into the cavernosal spaces, leading to increased intracavernosal pressure and penile erection. It is specific for receptors in the penile corporal smooth muscle; however, such receptors are also present in the retina.⁸⁸ The onset of penile tumescence occurs within ten to 40 minutes after oral administration.

Sildenafil is available as 25 mg, 50 mg, and 100 mg tablets. The recommended dose is 50 mg taken orally one hour before sexual activity. Based on response and side effects, the dose may be increased or decreased. The maximum recommended daily dose is one tablet. Sildenafil is contraindicated in patients who are taking nitrates as it may potentiate the hypotensive effects of nitrates.¹¹³

The product information for sildenafil mentions that 21 randomized, double-blind, placebo controlled studies of up to 6 months duration have been completed. The outcome of these studies has been consistent, statistically significant improvements for measured variables for sildenafil compared to placebo.¹¹⁴

Sildenafil has been found effective in patients with a history of coronary artery disease, hypertension, other cardiac diseases, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft, radical prostatectomy, and spinal cord injury, according to labeling.¹¹³ A study conducted in twelve patients with erectile dysfunction of no established organic cause was performed to examine the efficacy and safety of sildenafil.⁸⁸ Patients aged 36 to 63 years, were entered into a double-blind, randomized, placebo-controlled, crossover study. At-home efficacy was assessed by a diary record of penile erectile activity after single daily sildenafil or placebo doses for 7 days. From the diary record of daily erectile activity, the mean total number of erections was significantly higher in patients receiving sildenafil (6.1) compared to the placebo group (1.3). Ten of 12 patients reported improved erectile activity while receiving sildenafil, compared with two of 12 on placebo. Six patients on active treatment and five on placebo reported mild and transient adverse effects which included headache, dyspepsia, and pelvic musculo-skeletal pain.

Several recently published studies have further demonstrated sildenafil’s efficacy and side effect profile. In a study by Buvat et al, 311 patients received sildenafil for 1 year in doses starting at 25 mg, with the option to reduce the dose to 10 mg or increase incrementally to 50 mg and then to 100 mg.⁸⁹ A total of 271 (87.1%) patients continued treatment at one year; only 13 (4.2%) withdrew due to lack of efficacy. Twelve patients withdrew due to adverse effects, but only 3 patients had confirmed adverse effects due to sildenafil. The most frequently reported adverse events were headache, facial flushing, and indigestion.

In another report, sildenafil was evaluated in male outpatients with erectile dysfunction (73% organic, 9% psychogenic, and 18% mixed) when administered as needed one hour prior to anticipated sexual activity.⁹⁰ Patients received either placebo, 5, 25, 50, or 100 mg of sildenafil in an eight week follow-up. All doses were found superior to placebo, with a dose-escalating effect seen. Adverse effects included headache, vasodilation, dyspepsia, and diarrhea, which were predominately mild.

In a study of 27 patients with erectile dysfunction due solely to spinal cord injury, no patients discontinued treatment due to adverse events while 65% of patients on sildenafil had penile base rigidity significantly greater than placebo as measured by Rigiscan^®.⁹¹

To review, sildenafil given orally should offer an effective alternative to intracavernous or intraurethral pharmacologic interventions, as well as to vacuum devices and surgery. The side effect profile appears tolerable in most patients.

Yohimbine—Yohimbine is an indole alkaloid obtained from the bark of the yohimbine tree. The drug was "grandfathered" by the Food and Drug Administration (FDA) in 1976, bypassing controlled trials to demonstrate efficacy and safety in treating erectile dysfunction.⁷⁹ Yohimbine acts as a presynaptic alpha-2 adrenoceptor blocker with central and peripheral effects.⁸⁰ By blocking alpha-2 adrenoceptors in the brain, yohimbine produces an increased sympathetic drive that may enhance peripheral mechanisms that stimulate the erectile process. It may also have direct alpha-2 blocking action in the penile tissue leading to smooth muscle relaxation and enhanced blood flow. Once absorbed after an oral dose, the plasma half-life is approximately 30 minutes.⁵³

Yohimbine has been dosed in a number of different regimens, but commonly either as 5.4 to 6 mg three times daily or as a single dose of 6 mg given 40 to 60 minutes before intercourse.³⁵ The effectiveness of yohimbine has been the subject of debate. In one study, it was reported to induce satisfactory potency in only 14% of patients with mixed etiology erectile dysfunction, including diabetes. Success rates (measured as return of complete or partial erections) in other studies have ranged from 33 to 62%.^50,81-83 A clearer difference in the response to yohimbine was found in patients with a primarily psychogenic origin, with a positive response of 62% compared to 16% with placebo.⁸⁴

Yohimbine has been tried in combination with other oral medications.⁸⁵ When given with trazodone 50mg daily, a higher rate of positive results has been observed in patients with psychogenic erectile dysfunction with 72% of complete or partial responses, and 56% of patients still reporting a positive response at 6 months.

Based on results to date, the efficacy of yohimbine remains to be proven. However, a recent publication by Ernst and Pittler reviewed seven trials using meta-analysis. Overall, the authors found yohimbine to be superior to placebo in the treatment of erectile dysfunction and that serious adverse reactions were infrequent.⁸⁶ One must remember, however, that many yohimbine products are not regulated to the same extent as prescription agents and therefore not subject to the same strenuous quality assurance standards. Yocon^® (Palisades Pharmaceuticals, Inc) is a prescription product that contains 5.4 mg of yohimbine per tablet. Adverse effects consist mainly of sympathetic stimulation. These include palpitations, fine tremor, and slight elevations in blood pressure. Other adverse effects include dizziness, anxiety, nervousness, insomnia, nausea, headache, flushing, and muscle cramps.

Trazodone—Trazodone’s mechanism of action to improve erectile function is not known. It is a serotonergic agent that acts centrally by increasing serotonin at the 5-HT receptor through reuptake inhibition. It may also function peripherally as an alpha-adrenergic blocking agent, resulting in relaxation of the penile vascular bed and interfering with the sympathetic control of penile detumescence.¹⁵ Doses of trazodone for erectile dysfunction range from 50 mg to 200 mg daily. When used alone, trazodone has been shown to produce positive responses in more than 60% of patients.⁸⁷ Trazodone may cause drowsiness and sedation. The dosage should be slowly titrated to achieve the optimal response.

Pentoxifylline—Pentoxifylline decreases red blood cell membrane rigidity making the cells more flexible, allowing them to pass more readily through partially obstructed arteries. Use of pentoxifylline in erectile dysfunction is limited to patients with penile vascular disease. It has been demonstrated to restore potency in some males with early penile vascular disease.^92,93 In a placebo-controlled study using oral pentoxifylline 400 mg three times daily, the majority of patients had a significant improvement in the penile vascular blood flow, but there was no significant effect in improving erectile function.⁹⁴

L-arginine—L-arginine is an amino acid precursor to nitric oxide with limited evidence to support its use in treating erectile dysfunction. In one study, 15 patients received 2800 mg given orally daily. Six indicated improvement in the quality of their erections. These patients had psychogenic or mild vasculogenic erectile dysfunction.⁹⁵ The study found L-arginine to be relatively free of side effects.

Phentolamine—Phentolamine is the alpha-adrenergic agonist used mainly for intracavernous vasoactive injection in combination with other vasodilating agents. Systemic administration may have erectogenic properties by direct effect on the corpus cavernosum and by a central antianxiety effect.⁵⁰

A study examined the effectiveness of oral phentolamine to improve erectile dysfunction. With a dose of 50 mg, 68% of patients with erectile dysfunction of various etiologies had a desired response.⁹⁶

Giving phentolamine via the buccal route was studied in an attempt to reduce systemic side effects. The amount used in studies varied between 20 and 40 mg of phentolamine impregnated on a strip which was applied to the oral mucosa about 15 minutes before intercourse. Patients with mild or psychogenic vascular erectile dysfunction had a response rate from 20 to 40%. These studies are small and preliminary.¹⁵ Adverse effects include stuffy nose, faintness, dizziness, and burning of gums. Avoid using in patients with severe ischemic heart disease, hypertension, or other cardiovascular diseases. At this point, phentolamine orally is not used in the clinical setting.

HORMONE MANIPULATION
Testosterone—When erectile dysfunction is accompanied by hypogonadism, testosterone treatment may be initiated. Supplemental androgens should be prescribed only to individuals with documented hypogonadism. A diagnosis of hypogonadism should be based on consistently documented abnormally low levels of free serum testosterone associated with diminished libido.^1,5

Longer acting intramuscular injections are preferred such as testosterone cypionate or testosterone enanthate. The standard dose is 300 mg every 3 weeks. Levels are usually supraphysiologic during the first week after injection. If an older patient complains of urinary symptoms from an enlarging prostate, the dose can be decreased to 200 mg and given every 2 weeks. The long-acting parenteral esters, testosterone cypionate and enanthate, are considered drugs of choice for replacement therapy. Testosterone enanthate 250 mg given IM every 2 to 3 weeks is often used. The shorter-acting testosterone propionate requires multiple weekly injections.^1,5,15

Testosterone transdermal patches applied to the scrotum (Testoderm^®, Alza) or to the back, abdomen, or upper arms (Androderm^®, SmithKline Beecham) are available for the treatment of hypogonadism. One study, which assessed nocturnal erections using the Rigiscan^® device and patient reports, demonstrated sexual function improved significantly in men with hypogonadism treated with testosterone transdermal systems.¹¹² The patches offer useful alternatives for patients taking anticoagulants and those who want to avoid the muscle hematomas that intramuscular injections might cause. Oral androgenic steroids have been associated with adverse events such as hepatotoxicity and are often ineffective.^1,97

Bromocriptine—Bromocriptine is a dopaminergic agent. Its major effect is to reduce the production of prolactin and is used primarily in the treatment of prolactinomas. Hyperprolactinemia is frequently associated with hypogonadism.¹ About 2 to 5% of patients with erectile dysfunction have hyperprolactinemia. It is most often related to patients taking medications associated with overproduction of prolactin (estrogens, methyldopa, or large doses of a phenothiazine or reserpine). Another cause is pituitary tumors, most of which are microadenomas which respond to bromocriptine. Bromocriptine is given daily in divided doses starting with small doses and increasing to between 5 and 7.5 mg after tolerance has been established. Patients may also require androgen replacement therapy.

INTRACAVERNOSAL INJECTION
First reported in the early 1980s, intracavernosal injection of vasodilating agents has become an accepted standard for the treatment of erectile dysfunction.¹ Intracavernous administration of vasoactive drugs directly activates the vascular mechanisms of penile erection. The most studied agents are papaverine hydrochloride, phentolamine, and alprostadil, used singularly or in combination. Intracavernosal injection of these substances appears to work for the treatment of mixed, idiopathic, and organic erectile dysfunction. It is effective for patients with neurogenic problems, such as those with spinal cord injuries. It is least effective in men with severe veno-occlusive dysfunction or arterial insufficiency, although some patients may respond to multidrug mixtures.⁵⁰ Self-injection may even serve as an adjunct therapy to psychological intervention.³⁷

Overall, intracavernosal injections are effective in approximately 70 to 80% of patients.⁵¹ Candidates should be motivated and capable of performing injections or have a partner willing to perform them. Patients need to be medically stable. Patients with severe cardiovascular or cerebrovascular disease are usually not good candidates to use intracavernosal injections due to systemic absorption and side effects. Also, patients with sickle cell disease, Peyronie’s disease, or severe bleeding disorders (or on anticoagulation therapy) probably are not good candidates due to concerns of priapism and bleeding. Also, patients with poor manual dexterity, poor visual acuity, or morbid obesity may not be good candidates.

The goal is to provide an erection that is sufficient in duration to allow satisfactory sexual activity but not longer than one hour. Patients must be cautioned about the possibility of a prolonged erection, defined as lasting longer than four hours or a painful erection of shorter duration.

When the patient and physician agree that self-injection therapy will be tried, treatment is initiated in the clinic office. The program starts with a test dose of an agent or mixture of agents to determine erectile responsiveness. The dosage is increased at subsequent clinics, as needed, until an adequate response is achieved. A lower dose may be recommended if a maximal erectile response is reported during initial testing.

Generally, the self-injection technique involves the following procedures.³⁵ After proper skin cleansing, the patient should be asked to occlude the venous drainage by apply the index and middle finger to the base of the penis. The injection can be given into either cavernosal body (either side of the penis) through a 25 to 27 gauge needle. It should be injected laterally (into the side) to avoid trauma either to the dorsal vein or to the urethra. Response can be enhanced by standing up and massaging the penis. Patients are instructed to limit injection use to three times a week, with no more than 1 injection in any 24 hour period. They are also taught to alternate cavernous body injections.

Self-injection therapy should be initiated only after the patient’s competence in the procedure has been demonstrated during the office visit, and follow-up should be continuous. The drop-out rate in patients using self-injection is fairly high and complications can occur such as prolonged erection and corporal fibrosis and tunical nodule formation. The use of newer medications and more careful patient education and supervision can decrease the occurrence of problems and improve the efficacy and safety.⁵²

Papaverine—Papaverine (Cerespan^®) is a smooth muscle relaxant that is an alkaloid obtained synthetically or from opium. It acts on the smooth muscle to cause inhibition of phosphodiesterase, leading to an accumulation of cyclic adenosine monophosphate and smooth muscle cell relaxation. It facilitates erection by relaxation of smooth muscles in the sinusoids and by dilatation of the helicine arteries.⁵³ The plasma half-life of papaverine is 1 to 2 hours and it is extensively metabolized in the liver. Papaverine reaches a maximum concentration in the circulation within half an hour after intracavernosal injection.^35,53

The intracavernosal dose may vary with age and etiology of erectile dysfunction, from 10 mg initially to a maximum of 60 mg for older patients with vasculogenic erectile dysfunction.³ When given in combination with phentolamine, the dose is reduced.³⁵ The number of responders to papaverine monotherapy is reported to be low, about 35%, compared to 65% when combined with phentolamine.⁵⁴

Patients should be monitored for prolonged erections. Prolonged erection when papaverine is used alone is seen in up to 10% of patients.⁵³ Local complications such as subcutaneous hematomas and pain occur. Longer-term use of intracavernous injections of papaverine may induce corporeal fibrosis, corporal nodules, and plaques or fibrosis. This may be due to the acidity of papaverine solutions (pH 3 to 4) which cannot be corrected by the use of a buffer due to precipitation at a pH greater than 5.50.

Systemic effects include vasovagal reaction, bradycardia, hypotension, dizziness, and facial flushing. Papaverine is potentially hepatotoxic.⁵⁰ The incidence of drug-induced hepatitis is less than 1 in 1000 in patients with normal liver function, but may be seen in 1 of 100 patients with existing elevated transaminase levels.

Phentolamine—Phentolamine mesylate (Regitine^®) is an alpha-adrenergic receptor blocker. By blocking sympathetic activity on smooth muscle, phentolamine causes dilation of penile arterial vessels. Phentolamine is not very effective for the treatment of erectile dysfunction when used as intracavernosal injection monotherapy. It is usually given in combination with other agents such as papaverine and alprostadil. After intracavernosal injection, phentolamine reaches a maximum serum concentration within 30 minutes, and declines rapidly to undetectable levels.⁵³ Phentolamine has a short plasma half-life of 30 minutes and is extensively metabolized by the liver. The amount of phentolamine used for intracavernosal injection mixtures commonly varies from 0.5 to 20 mg, with a usual dose around 1 to 2 mg. Systemic adverse effects may include orthostatic hypotension and tachycardia. These effects are reduced when used in lower-dose combinations with other vasoactive agents.

Prostaglandin E1 or Alprostadil—Alprostadil, or PGE1, is an analogue of arachidonic acid. Alprostadil has alpha-blocking properties in the penile tissue which causes relaxation of the cavernous and arteriolar smooth muscle while causing restriction of venous outflow. Alprostadil is the only injectable medication formally approved for the treatment of erectile dysfunction. The two products available are Caverject^® (Pharmacia-Upjohn) and Edex^® (Schwarz Pharma). It can be used either as monotherapy or in lower doses in combination with other vasoactive agents. Alprostadil that enters systemic circulation is quickly metabolized, primarily by the lungs.³⁵ The plasma half-life of alprostadil is less than one minute.

The initial dose is usually 2.5 mcg. The dose is increased, if necessary, on subsequent office visits until a satisfactory response is obtained. The goal is to produce an erection that is satisfactory for sexual activity and is maintained for no longer than one hour.^35,50 The maximum recommended dose is 40 mcg for Edex^® 55 and 60 mcg for Caverject^®.⁵⁶ The average therapeutic dose is higher in older compared to younger men (21 mcg versus 12.5 mcg, respectively).³ This is likely because of the higher prevalence of arterial occlusive disease in older people. In a study by Garceau et al,⁵⁷ the average effective dose of alprostadil differed depending on the cause of erectile dysfunction; in men with vascular causes, the dose averaged 19.1 mcg; psychogenic causes, 11.5 mcg; and neurogenic causes, 15.3 mcg. The efficacy of alprostadil has been documented to be about 75% in doses between 10 to 20 mcg intracavernously, with doses as low as 2.5 to 5mcg occasionally being effective.⁵³ Patient and partner satisfaction after injection was reported in up to 87% of partners.⁵⁸

Using appropriate injection technique, alprostadil should produce an erection in five to twenty minutes. It is recommended not to inject more than three times per week and to separate each use by at least 24 hours. The patient should been examined by a physician every 3 months during self-injection therapy to assess treatment and to adjust the dose if needed.

A major advantage of alprostadil over other intracavernosal injection agents is the very low risk for the induction of prolonged erections.⁵⁹ The risk of developing prolonged erection and priapism after alprostadil injection is about 1.3%.⁶⁰ The low incidence may be due to the process of local metabolism of alprostadil by prostaglandin dehydrogenase.⁵³ Alprostadil may have an antifibrotic effect, which may explain a low incidence of nodule and fibrosis formation.

Pain is the primary side effect of alprostadil injections. Pain has been reported in a wide range of patients (13 to 80%) and is dose related, occurring more frequently at doses greater than 15 mcg.^50,61 The general dropout rate due to penile pain was reported to be 2 to 11% in one study.⁶⁰ This may be related to characteristics of prostaglandins of the E group in sensitizing special pain receptors in penile tissue.⁵⁸ To avoid the pain, 7.5% sodium bicarbonate or procaine 20 mg has been added by some investigators to an alprostadil solution.⁵⁰

A potential advantage of intracavernous injection of alprostadil may be recovery of spontaneous erections following surgery for prostate cancer. In a small study, 67% of patients who received alprostadil injections three times weekly for 12 weeks reported recovery of spontaneous erections at the 6 month follow-up compared to a 20% recovery rate in a group receiving standard follow-up care.⁶²

Injection of Combinations of Vasoactive Agents—Vasoactive agents can be combined in solution to utilize the synergistic effect derived from different mechanisms of action which produce erectogenic effects. Patients with severe penile vascular impairments, especially those with marked veno-occlusive dysfunction of the corpora cavernosa, are typically poor responders to single drug intracavernous injection therapy.⁵⁰ These patients tend to have a better response to combination injections. In addition, adverse effects of all agents are dose dependent. When used in combination, the dose of each agent is lowered thereby decreasing the chance for an adverse effect.⁵²

A common two drug combination is phentolamine and papaverine. In one study, this combination provided roughly the same response rate as alprostadil alone.⁶¹ A combination of three agents, papaverine, phentolamine, and alprostadil is often used for patients who are nonresponders to single or two drug combinations. This combination is often referred to as "trimix." An example of a trimix solution is 15 mg of papaverine, 0.5mg phentolamine, and 5 to 10 mcg of alprostadil, for a total injected volume of 1 to 2 ml. The success rate of the trimix combination has been reported to be 92%.⁶³ The risk of prolonged erection and priapism is said to be less with this combination, with reported rates of 1.7%⁵² and between 3 to 5%.⁶¹ Two recent abstracts examined patient preferences and satisfaction between trimix and alprostadil intracavernous injections. In both studies, the trimix solution was favored by more patients than alprostadil.^64,65 A four drug combination of papaverine, phentolamine, alprostadil, and atropine, had a reported response rate of 95%.⁶⁶

Cautions With Intracavernosal Injection Therapy—Problems associated with penile injections of these agents include pain, penile corporal fibrosis, fibrotic nodules, hypotension, prolonged erections and priapism.^60,67 Use of intracavernosal injection therapy can be a problem in patients who cannot tolerate transient hypotension; those with severe psychiatric disease, poor manual dexterity, or poor vision; and those receiving anticoagulant therapy.⁵⁰

While intracavernosal injection is an effective approach to restoring erectile function, there is a high dropout rate (40 to 50%).^68,69 It is unclear as to why, but it may be related to side effects, lack of spontaneity in sexual relations, or general loss of interest. Patient education and follow-up support should improve compliance and lessen the dropout rate. Interestingly, in one study of dropouts, the most frequent reason given was recovery of spontaneous erectile function.⁷⁰

Treatment of prolonged erection and priapism—Prolonged erection (erection >3 hours) and priapism (erection longer than 6 hours) is a problem with self-injection. Priapism or prolonged erections are usually encountered during the dose titration phase and have been reported in 0.5 to 15% of patients, depending on the vasoactive agent and the patient’s underlying medical issues.^50,60,67 Patients must be instructed and understand what steps to take when these conditions occur to avoid any long-term effects. Usually patients are instructed to go to an emergency room if an erection persists for longer than 3 hours. If an erection lasts for more than 6 hours, there is a danger that intracavernosal hypoxia may occur, resulting in fibrosis of the trabecular smooth muscle and possibly preventing future erections.

Initial simple measures like putting the patient in a cold bath, asking him to use an exercise bike or making him run up and down stairs can be effective.^35,53 If the simple measures do not work, the next step is to remove blood from the corporal cavities by aspirating 10 to 20 ml of blood from one corpora cavernosum via an 18 or 20 gauge needle and then injecting a solution of phenylephrine. The patient’s blood pressure and pulse should be monitored during this procedure.^71-73

INTRAURETHRAL ALPROSTADIL
Alprostadil (PGE1) is also available in a suppository dosage form that is inserted into the urethra. The product is called MUSE^® (Medicated Urethral System for Erection, VIVUS, Inc). The intraurethral alprostadil system does not require the use of a needle and is therefore preferred by some patients over the injection therapy. When sexual activity is anticipated, the patient inserts a small applicator into the urethra after urinating. The applicator then dispenses a small suppository about three centimeters into the urethra. Alprostadil is absorbed locally and produces intracorporeal smooth muscle relaxation.^50,74 Intraurethral alprostadil has shown to begin the erectile process in five to 10 minutes after administration with a duration of 30 to 60 minutes.⁷⁵ It is available in doses of 125 mcg, 250 mcg, 500 mcg, and 1000 mcg. The lower strengths are recommended for initial dosing, which is initiated in the clinic setting. Once an acceptable dose has been achieved, the patient should use no more than two systems per 24 hour period. The patient must not lie down immediately after administration of the drug. Rather, he must walk or stand for about 10 minutes to increase penile blood flow.

The most serious local side effects in clinical trials were priapism and prolonged erection, seen in less than 0.1% and 0.3% of patients, respectively. The most frequently reported side effect in clinical trials was penile pain, reported at least once by 36% of patients in clinic and 32% of patients at home.⁷⁴ Other possible problems include urethral burning in the patient (12%) and minor urethral bleeding or spotting (5%).⁷⁶ Vaginal burning or itching was reported by 5.8% of partners. It should not be used for sexual intercourse with a pregnant women unless the couple uses a condom. The initial dosing should be done in a clinic setting because of the potential for symptomatic hypotension and syncope, which has occurred in 3 and 0.4% respectively. The intraurethral alprostadil is contraindicated in men with abnormal penile anatomy, with conditions that predispose to priapism, and in whom sexual activity is inadvisable.

In studies of over 1500 patients in total, transurethral alprostadil was able to achieve good overall erectile response in 66 to 75% of patients.^77,78 The most common side effect was penile pain, ranging from 11 to 18% depending on the dose used. There were no reports of priapism.

TOPICAL
Minoxidil—Minoxidil is a vasodilator agent that acts directly on arterial smooth muscle. Primarily used as an alternative treatment for hypertension as well as for specific forms of alopecia, minoxidil has been studied for the treatment of erectile dysfunction using topical preparations. It is thought that when applied topically, minoxidil causes dilation of the penile arteries and relaxation of the smooth muscle of the corpora cavernosa. A few studies provide mixed evidence of the effectiveness of minoxidil to induce erections. In one, a 2% solution of minoxidil applied in a dose of 1 ml to the glans penis caused greater changes in penile tumescence, rigidity, and arterial function than did administration of 2.5 gm of 10% nitroglycerin ointment and placebo.⁹⁸ In the clinical setting, the same doses of minoxidil appeared to be of minimal benefit.^99,100 Adverse effects after topical administration of minoxidil were minimal and included a burning sensation of the glans penis in some patients.

Nitroglycerin—Nitroglycerin, administered topically in the paste form, may increase nitric oxide concentration in penile tissue leading to relaxation of the cavernosal artery smooth muscle. When used for the treatment of erectile dysfunction, nitroglycerin paste is applied either to the penis or on the perineum. It results in partial or full erections in patients with neurogenic, psychogenic, and organic causes of erectile dysfunction.^101,102 However, response rate is less than with other interventions.¹⁰³

The usual dose is 2 cm (1 inch) of the 2% paste applied topically. The ointment is applied 30 to 60 minutes before intercourse. It is important to use a condom to prevent the transmission of the drug to the partner. Application of nitroglycerin ointment to the perineal area exclusively causes erectile responses similar to those observed after genital application, obviating the need to wear a condom.¹⁰¹ Side effects include hypotension and severe headache. Partners may also suffer from similar side effects.

Papaverine—The effect of topical papaverine in the form of 7.5, 15, and 20% gels has been assessed in a small trial. After application to the scrotum, perineum, and penis of 20 patients with organic erectile dysfunction, cavernous artery diameter was significantly increased in most patients. However, full erections were present in only 15% of patients and were present in the placebo group as well.¹⁰⁴ Adverse effects were minimal.

Devices

VACUUM DEVICES
Vacuum constriction devices may be effective at generating and maintaining erections in many patients with erectile dysfunction. Many patients with erectile dysfunction may be eligible candidates for vacuum therapy, as this treatment has a high effectiveness rate regardless of the etiology of erectile dysfunction .^35,105

A vacuum constriction device consists of a cylinder placed over the penis using a lubricant to achieve a good seal between the body and the cylinder. A vacuum is created inside the tube using a pump. The vacuum helps the corpora cavernosa engorge with blood, creating an erection. This is followed by the placement of a constriction ring at the base of the penis to sustain the erection during intercourse. The band must be removed after 30 minutes.⁷⁹ It must be tight enough to maintain penile rigidity, but not so tight as to injure the penis. The penis may pivot at the point of constriction, which may require the patient to stabilize the penis during sexual intercourse. Partner involvement in training with these devices may be important for successful outcome, especially in establishing a mutually satisfying level of sexual activity.

The initial overall response rate with these devices is 80 to 90%. Longer term studies show satisfaction rates approaching other interventions, and are closer to 50 to 70%.¹⁰⁶

Some reported side effect include occasional numbness, pain, penile bruising, or petechiae.³ The devices may also cause premature ejaculation or pain during ejaculation. Some partners have complained that the penis feels cold. A major drawback of these devices is the necessity for precoital application and thus acceptance by the partner is important. There is a significant rate of patient dropout with these devices, and reasons are unclear. The devices are difficult to use by some patients, especially those with impaired manual dexterity.

Patients who may have a tendency to develop priapism may not be good candidates for use of these devices. Likewise, patients with bleeding disorders should probably not use these devices.⁵¹ Patients who have severe penile scarring of the corpora cavernosa from priapism or a severe intracavernosal infection due to penile implants, may not obtain full penile engorgement with these devices. Some patients with Peyronie’s disease who have a severe curvature with penile erection cannot use the vacuum device because of lack of freedom of movement of the penis within the vacuum cylinder.¹⁰⁵

VENOUS FLOW CONSTRICTION
In patients with veno-occlusive incompetence, an erection may be obtained but lost due to leakage of blood from the cavernosal spaces due to lack of closure of the venous outlet system. A band, like those used with vacuum devices to restrict venous blood outflow, can be placed on the base of the penis to maintain an erection. Penile bands should be used for no longer than 30 minutes. Problems that may occur include difficulty applying and removing the band as well as pain.

IMPLANTED PROSTHESIS
Penile prostheses can be surgically implanted in the corporal cavernosa of the penis. There are three types of prostheses for patients who fail with or decide against other forms of therapy. These include the semirigid, malleable, and inflatable prostheses. The semirigid rod is the same size at all times but may be bent either up or down as desired. The malleable implants are rods that can be flexed or straightened.

Inflatable prostheses remain flaccid until a pump located in the scrotum moves fluid from a retropubic reservoir into the prosthetic penile cylinders. These devices have a high rate of patient satisfaction. Most prostheses can be expected to last from seven to 10 years and most failures can be successfully corrected to give five to 10 more years of function.¹⁰⁷ The effectiveness, complications, and acceptability vary among the three types of prostheses, with the main problems being mechanical failure, infection, and erosions.^1,23 There is a risk for reoperation with all devices. The inflatable prostheses may provide a more physiologically natural appearance, but they have a higher rate of failure requiring reoperation. Men with diabetes mellitus, spinal cord injuries, or urinary tract infections have an increased risk of prosthesis-associated infection.

Vascular surgery

A number of surgical techniques to correct arterial blockage or venous leakage have been developed with varying success. Surgery of the penile venous system, generally involving venous ligation, has been reported to be effective in patients who have demonstrated to have venous leakage.¹ Arterial revascularization procedures have a limited role in congenital or traumatic vascular abnormalities. Revasuclarization is reserved for men less than 60 years of age without diabetes, and diagnosed as having arteriogenic impotence. Traumatic etiologies of erectile dysfunction have the best success rate. These surgeries have been performed on only a small number of patients around the world and are considered experimental at this time.¹

A German group has reported its experience with percutaneous transluminal angioplasty in 19 males with erectile dysfunction under age 50 years with moderate and limited arteriogenic stenosis. They had an 84% success rate, with potency returning within 3 days to 2 weeks after percutaneous transluminal angioplasty.²²

COUNSELING PATIENTS WITH ERECTILE DYSFUNCTION

Pharmacist-patient communication can help patients understand what their medicine is used for, how to use it, and what to expect from it. This is no less true for the patient with erectile dysfunction.

Educating patients and reassuring them may be helpful. The quality of the pharmacist-patient relationship may facilitate the recognition and treatment of erectile dysfunction. The continuity of care provided by a pharmacist may encourage patients to present problems to their pharmacist. Likewise, the presence of an established relationship may make it more comfortable for pharmacists to include questions about sexual functioning in the process of medication history taking. The relationship also provides a foundation for improving patient compliance.

Pharmacist comfort in discussing sexual issues with patients and the desire to assist patients with sexual problems will vary. History taking skills and current knowledge regarding the causes and treatment options for erectile dysfunction will vary among pharmacists. However, if pharmacists do nothing more than identify sexual dysfunction in patients and recommend the patient see their physician, many patients will benefit.

Discussing subjects as personal as sexual function can be difficult. Many male patients will not spontaneously volunteer information about the presence of a sexual dysfunction. Patients may be embarrassed, afraid of wasting a pharmacist’s time, or misinformed about causes and treatments. Many patients will, however, discuss the issue when asked by a health professional.

During a medication history interview with a patient who takes medication known to be related to sexual dysfunction or who has a disease know to be related to erectile dysfunction, the pharmacist can ask a open-ended question regarding sexual function. An example of a question(s) can be framed generally, such as "Do you have any problems with sex that you think might be related to your medications" or more targeted such as "Some patients taking _____ medication may experience sexual problems. Have you experienced this type of problem?" These questions indicate to the patient the pharmacist’s willingness to discuss the issues. Asking general and non-threatening questions allows the patient to describe and reflect on his sexual functioning. "Are you experiencing any sexual problems or concerns?" is another general opening question.

To facilitate an interview, the pharmacist should provide an interviewing area where conversation with the patient can be confidential. The pharmacist should have an empathetic approach to the interview. This approach gives the patient the impression that the pharmacist is truly concerned about their welfare and is willing to help. This approach may enhance the patient-pharmacist relationship. When counseling the patient on medications being dispensed, it is vital that the pharmacist not only provide the patient with complete and accurate information, but also check for patient comprehension of the information. This is accomplished by periodically asking the patient to repeat back key points. In this way, the pharmacist can enhance patient understanding of the medication and its proper use.

CONCLUSION

Erectile dysfunction is a common problem. The treatment of patients requires a sensitive approach by all health care providers and includes taking into account the needs and aspirations of each patient. New oral treatments are being developed that, for many patients, will be an alternative to intracavernous injections, vacuum devices, or surgery. Pharmacist can play an active role in identifying patients in the outpatient setting who may benefit from these interventions.

Questions:
Assessment Questions.

1. The term erectile dysfunction refers to which of the following?
(A) Reduced sexual desire (libido)
(B) Inability to attain and maintain an erection sufficient for sexual intercourse
(C) Premature ejaculation
(D) Inability to achieve an orgasm
(E) a and d are both correct

2. It is estimated that in the United States, ____________ men are affected with mild to severe erectile dysfunction.
(A) 10 million
(B) 30 million
(C) 100,000
(D) 1 trillion
(E) 60 million

3. Despite the high prevalence of erectile dysfunction less than _____ % of those affected receive treatment.
(A) 5
(B) 10
(C) 15
(D) 50
(E) 80

4. The erectile tissue of the penis consists of three chambers. They are know as the:
(A) Corporal cavernosa
(B) Corporal spongiosum
(C) Tunica albuginea
(D) Helicine arteries
(E) a and b are both correct

5. Parasympathetic stimulation causes relaxation of the smooth muscle of the penile trabecular tissue. This action is mediated by:
(A) Nitric oxide
(B) Norepinephrine
(C) Dopamine
(D) Interleukin-1
(E) None of the above are correct

6. A 53 year old male complains of erectile dysfunction. He has no medical problems. His first wife passed away 5 years ago and he has recently remarried.
The initial workup indicates no vascular or hormonal abnormalities. The erectile dysfunction could be categorized as most likely being:
(A) Neurogenic
(B) Drug induced
(C) Psychogenic
(D) Allogenic
(E) None off the above are correct

7. Which of the following general classes of medications may cause or contribute to erectile dysfunction?
(A) Antihypertensives
(B) Antipsychotics
(C) Cephalosporins
(D) Non-sedating antihistamines
(E) a and b are both correct

8. Which of the following statements below describe the principle of goal-directed therapy?
(A) Before a treatment is considered successful for a patient it must induce an average of five nocturnal erections as measured by a Rigiscan® device during a dose titration period.
(B) The patient is informed of all treatment options, costs, and consequences.
(C) The patient's (and when possible the partner's) expectations and desires are taken into account when formulating a treatment plan.
(D) Many diagnostic tests may not be necessary depending on the treatment chosen by the patient
(E) b, c and d are correct answers

9. Which of the following are patient-related characteristics that make the use of intracavernous injections either a relative or absolute contraindication?
(A) Sickle cell disease
(B) Peyronie's disease
(C) Taking warfarin anticoagulation therapy
(D) Poor manual dexterity due to a stroke
(E) All the above are correct answers.

10. Which of the following agents are commonly used either alone or in combination for intracavernous injections?
(A) Alprostadil
(B) Phenylephrine
(C) Phentolamine
(D) Papaverine
(E) a, c, and d are all correct

11. Which of the following agents has good efficacy when used as intracavernous injection mono-therapy?
(A) Alprostadil
(B) Papaverine
(C) Phentolamine
(D) Atropine
(E) None of the above

12. A goal of intracavernous self-injection is to produce an erection that lasts for _____ hour(s).
(A) 4 hours
(B) 1 hour
(C) 0.5 hour
(D) 3 hours
(E) 6 hours

13. Potential complications of intracavernous injections include:
(A) Penile pain
(B) Corporal fibrosis
(C) Prolonged erections
(D) Hypotension
(E) All the above are correct.

14. Of the following oral medications used for the treatment of erectile dysfunction, which is the only one with FDA approval at this time?
(A) Trazodone
(B) Yohimbine
(C) Sildenafil
(D) Pentoxifylline
(E) Phentolamine

15. Sildenafil's proposed mechanism of action is to increase ____________ concentrations in erectile tissue by blocking the enzyme type-V cGMP phosphodiesterase.
(A) Nitric oxide
(B) Dopamine
(C) Serotonin
(D) Norepinephrine
(E) Epinephrine

16. Which of the following are reported side effects of sildenafil?
(A) Headache
(B) Dyspepsia
(C) Pelvic skeletal muscle pain
(D) a, b, and c are all correct
(E) a and b are the only correct answers

17. Which of the following testosterone treatments is recommended for patients with erectile dysfunction and documented hypogonadism (low serum testosterone)?
(A) Testosterone cypionate intramuscular injection
(B) Testosterone transdermal patch
(C) Methyltestosterone oral tablets
(D) Testosterone enanthate intramuscular injection
(E) a, b, and d are all correct answers

18. Which of the following statements about vacuum constriction devices is (are) correct?
(A) Vacuum constriction devices are effective in most patients, regardless of etiology of erectile dysfunction.
(B) The constriction band that is placed at the base of the penis to maintain an erection after using the vacuum device must be removed after 60 minutes.
(C) Some reported side effects of using a vacuum device include numbness, penile pain and bruising
(D) a, b, and c are all correct
(E) a and c are the only correct answers

19. When counseling a patient who is at risk for having erectile dysfunction or who is receiving a newly initiated treatment for erectile dysfunction, the pharmacist:
(A) Should provide a private or semi-private area for counseling
(B) Should check for patient comprehension during the counseling session
(C) Could initiate discussion using an open ended question such as "Do you have any problems with sex that you think may be related to your medication?"
(D) Should conduct the counseling session using an empathetic, caring attitude.
(E) all of the above are correct answers.

20. Which of the following statements regarding surgical treatment for erectile dysfunction is (are) correct?
(A) Surgical implantation of penile prosthesis are considered first line therapy.
(B) Vascular surgery to correct arterial blockage or venous leakage is a common procedure that is a widely accepted treatment for erectile dysfunction.
(C) Patients with implanted prosthesis have a high rate of satisfaction with the devices.
(D) Patients with diabetes are the best candidates for implantation of penile prostheses.
(E) None of the above are correct statements.

Program Evaluation

21. How would you rate this educational program overall?
(A) Excellent.
(B) Very Good
(C) Good.
(D) Fair.
(E) Poor.

22. How well did this program achieve its educational objectives?
(A) Very well.
(B) Well.
(C) Somewhat.
(D) Not at all.

23. How well did this program improve your knowledge of the subject matter?
(A) Very well.
(B) Well.
(C) Somewhat.
(D) Not at all.

24. Will this be useful and relevant in your practice?
(A) Very useful/relevant.
(B) Useful and relevant.
(C) Somewhat useful/relevant.
(D) Not at all useful/relevant.

25. Do you think this CE program furnished:
(A) The proper amount of credit (2.0 hours).
(B) Not enough credit.
(C) Too much credit.